The control of bleeding during surgery is of considerable importance for the prevention of blood loss and the maintenance of a clear surgical field. For the prevention of gross bleeding from an exposed severed large artery or vein, where there is considerable intravasculr pressure, mechanical means, such as pressure or clamping, or cauterization are employed. For the control of bleeding from small blood vessels, where intravascular pressure does not prevent clotting, various methods may be used. One method comprises the topical application of thrombin to the wound surface whereby clotting is promoted by direct action of the thrombin of fibrinogen. Other methods employ substances which arrest bleeding by providing a mechanical matrix that facilitates clotting. Various absorbable substances used for this purpose are absorbable gelatin sponge (Gelfoam); oxidized cellulose (oxycel), or fibrin foam. A combination of such substances with thrombin (e.g. by saturating a pad of the absorbable substance with a thrombin solution) is especially effective.
The present invention provides an improved method for the attenuation of bleeding at a wound surface. The method comprises the topical application to the wound surface of an effective amount of prostaglandin derivative selected from the group consisting of:
A. 7-(5.alpha.-hydroxy-2.beta.-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-3.a lpha.-methyl-1.alpha.-cyclopentyl)cis -5-heptenoic acid; PA1 B. 7-(5.alpha.-hydroxy-2.beta.-[(3RS)-classes: -hydroxy-3-methyl-trans-1-octenyl ]-1.alpha.-cyclopentyl)-cis-5-heptenoic acid; and PA1 C. 7-(2.beta.-[(3RS)-hydroxy-3-methyl-trans-1-octenyl]-5-oxo-1.alpha.-cyclope ntyl)-cis-5-heptenoic acid.
The invention also contemplates the novel chemical compound:
7-(5.alpha.-hydroxy-2.beta.-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-3.al pha.-methyl-1.alpha.-cyclopentyl)-cis- 5-heptenoic acid.
Said compound is useful in the method hereinabove described.
Also contemplated by this invention is the chemical compound 7-[5.alpha.-hydroxy-3.alpha.-methyl-2.beta.-(3-oxo-trans-1-octenyl)-1.alph a.-cyclopentyl]-cis-5-heptenoic acid, which is useful as an intermediate for preparing 7-(5.alpha.-hydroxy-2.beta.-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-3-. alpha.-methyl-1.alpha.-cyclopentyl)-cis-5-heptenoic acid.
It is believed that the capacity of the compounds above-described to arrest bleeding is a consequence of their ability to promote platelet aggregation which is the initial step of the clotting process and is necessary for releasing platelet factors that act to convert prothrombin to thrombin. The method of the invention therefore, offers advantages in that the attenuation of bleeding is accomplished by a physiological process which avoids mechanical means and the introduction into the wound of a foreign protein (thrombin). It will be appreciated that the method is less effective in controlling bleeding from larger blood vessels where intravascular pressure might prevent clot formation. The method is especially useful to control bleeding from capillaries or small veins.
In practicing the method of the invention, the particular compound employed for the control of bleeding can be applied topically to the wound surface in a number of ways. The compound can be dissolved in a pharmacologically acceptable, non-toxic, aqueous sterile solution (such as physiological saline or physiological saline buffered to pH 7.4). The solution can be applied by irrigation or spraying. For such purposes, a syringe or an aerosol spray can be employed. Further, the compound, dissolved in a sterile solution, can be applied to a pad of an absorbable substance (absorbable gelatin sponge, oxidized cellulose, or fibrin foam) which is then placed on the wound surface. The pad acts as a preformed network to trap the blood, and it can be kept in place after closure of the wound since the pad is completely absorbed in 4 to 6 weeks.
When the compounds are applied dissolved in an aqueous solution, the active ingredient can be present at a concentration of from about 50 to about 1000 .mu.g/ml. A concentration of from about 200 to about 500 .mu.g/ml is preferred.
The amount of compound required to effect attenuation of bleeding will vary with the size of the wound surface, the source of the bleeding, and the severity of the bleeding. In general, the compound is applied in small incremental amounts until the desired attenuation is achieved.
The compounds utilized in the method of this invention are prepared from the known starting materials PGA.sub.2 or 15-epi-PGA.sub.2. 15-epi-PGA.sub.2 can be obtained from the coral Plexaura homomalla by a procedure as described by A. Weinheimer and R. Spraggins in Tetrahedron Letters, 59, 5185 (1969), and PGA.sub.2 can be prepared from 15-epi-PGA.sub.2 by an epimerization procedure as described by Bundy et al. in Ann. of the New York Acad. of Sci., 180, 76 (1971). 7-(5.alpha.-Hydroxy-2.beta.-[(3RS)-3-hydroxy-3-methyl-trans-1-oxtenyl]-1.a lpha.-cyclopentyl)-cis-5-heptenoic acid and 7(2.beta.-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-5-oxo-1.alpha.-cyclop entyl)- cis-5-heptenoic acid are described in U.S. Patent Application Ser. No. 383,007, filed July 26, 1973. The preparation of the compounds employed in the method of this invention from readily available starting materials is described below in Examples I to VIII.